Project Summary Women experience higher levels of craving and relapse during periods of drug abstinence, and take larger amounts of drug during bouts of relapse, as compared to men. Although this dfferential responding has been attributed to female's neuroendcrine functioning, the actual mechanim(s) underlying these sex differences are not well understood. Thus, the objective of the proposed research is to a) characterize sex differences in responseviness to cocaine, b) determine the role of estradiol (E2) and striatal membrane estrogen receptors (mERs) in cocaine reward, and c) in mediating cocaine-induced intracellular signaling within the nucleus accumbens (NAc). Our recent work demonstrates that females display higher levels of cocaine-primed reinstatement, as measured by conditioned place preference (CPP), than males. These data indicate that females form stronger associations between cocaine and the environment in which it was administered. We present data demonstrating sex differences in second messenger expression in NAc after reinstatement to cocaine-CPP, which can potentially explain differential behavioral responsivity previously observed. The proposed studies will complement and logically extend our previous work using behavioral, pharmacology, and molecular methods. First, we will examine our previous observations closer by subjecting intact male and cycling females to an extended CPP paradigm to examine sex and cycle differences in behavior and expression of three key molecular substrates important in forming drug reward associations in the NAc ? FosB, ERK and CREB. Second, we will complement these studies by directly manipulating E2 in gonadectomized (GDX) rats and subjecting them to the same CPP paradigm and biochemical measurements as above. Lastly, we will selectively block the mERs in NAc of GDX rats to determine sex specific roles of mERs in modulating the molecular events associated with sex differences in cocaine seeking behavior. Results from the proposed experiments will fill a large gap in our knowledge regarding interactions between E2 and brain reward circuitry associated with continual drug exposure. Clarification of the mechanisms by which E2 interacts with DA- mediated intracellular signaling to modulate the motivational salience of cocaine to influence drug-seeking behaviors may provide novel prevention and treatment strategies for women. Besides addressing a scientific issue of great importance, this proposal will also enrich student research experiences at the University of Texas, at Arlington. These studies will provide students from diverse backgrounds with meaningful and high quality early training opportunities in neurobiology, neuropharmacology and behavioral neuroscience, and increase their prospects for future careers in health-related sciences.